Drug interactions and cytotoxic effects of paclitaxel in combination with carboplatin, epirubicin, gemcitabine or vinorelbine in breast cancer cell lines and tumor samples

The purpose of this study was to analyze the drug interactions of paclitaxel (PTX) with epirubicin (EPI), carboplatin (CBDCA), gemcitabine (GEM) and vinorelbine (VIN) in human breast cancer cells and compare the cytotoxic activity of each drug combination in primary breast cancer samples. These experiments were intended to identify the most active agents in combination with PTX, and to provide a preclinical rational for future clinical investigations in breast cancer. Multiple drug effect/combination index (CI) isobologram analysis was applied to combinations of PTX with either CBDCA, EPI, GEM or VIN in MCF-7, MDA-MB-231 and SK-BR-3 human breast cancer cell lines. Drug concentrations were limited to the ranges achievable in humans in vivo, and the drugs were applied simultaneously at fixed molar ratios for each drug combination. Interactions were assessed at multiple effect levels (IC₁₀–IC₉₀). Additionally, the cytotoxic activity of these combinations was assessed in tumor samples of 50 primary breast cancer patients, utilizing the ATP-tumorchemosensitivity assay (ATP-TCA). Drug interactions were shown to be strongly dose-related in the human breast cancer cell lines investigated. At clinically relevant concentrations, CBDCA/PTX demonstrated synergistic (MCF-7) or additive (MDA-MB-231, SK-BR-3) interactions, and EPI/PTX showed additive (SK-BR-3, MCF-7) and antagonistic (MDA-MB-231) interactions. GEM/PTX and VIN/PTX, however, demonstrated antagonism over multiple dose effect levels at clinically relevant drug concentrations in all three cell lines tested. At plasma peak concentrations, EPI/PTX, CBDCA/PTX, GEM/PTX and VIN/PTX achieved 90% tumor growth inhibition in 93, 86, 63 and 50%, respectively, of primary breast cancer samples investigated with the ATP-TCA. Cumulative dose-response plots of primary breast cancer tumor cells responding in vitro with 90% growth inhibition showed a strong dose dependence for both EPI/PTX and CBDCA/PTX. In conclusion, the current data indicate favorable drug interactions for CBDCA/PTX at clinically relevant drug concentrations in breast cancer cells, and demonstrate superior in vitro cytotoxicity of EPI/PTX and CBDCA/PTX compared to GEM/PTX and VIN/PTX in primary breast cancer cultures.     

Progesterone receptor quantification as a strong prognostic determinant in postmenopausal breast cancer women under tamoxifen therapy

There is now an emerging body of evidence that shows there is a relationship between the survival of breast cancer patients and the expression level of steroid receptors. The aim of this study was to determine the relationship existing between estrogen receptors (ER) and progesterone receptors (PR) cytosolic content and the prognosis of postmenopausal breast cancer women under tamoxifen therapy. Two hundred and nineteen postmenopausal patients, without neoadjuvant chemotherapy and treated postoperatively with tamoxifen for at least 2 years, were followed up in our Cancer Center. We used flexible regression modeling and log likelihood methods for determining optimum cut-off values for steroid receptors, which allows the separation of patients into significantly different categories in term of survival. For PR, 3 categories were defined (category 1: PR < 10, category 2: 10 PR < 60 and category 3: PR 60 fmol/mg P). Univariate analysis at 8 years indicated that significant differences in event-free survival (EFS) were found for tumor size (T) (p = 0.005), lymph node status (N) (p = 0.003), histological Scarff, Bloom and Richardson grade (p = 0.003), ER values divided into 5 categories (p = 0.02) and PR values divided into 3 categories (p = 1 · 10^–5). Eight-year EFS rate for the 3 PR categories, adjusted for N, were 39, 66 and 81%, respectively. Multivariate Cox analysis indicated that only T, N and PR values were significant variables for EFS. Patients with PR values 60 present significantly greater EFS rates than patients with PR < 60 (p < 0.001). Our results show that the PR level in ER positive postmenopausal women is a strong prognostic marker in postmenopausal breast cancer women under tamoxifen therapy.     

Formestane, a steroidal aromatase inhibitor after failure of non-steroidal aromatase inhibitors (anastrozole and letrozole): Is a clinical benefit still achievable?

Background:There are few clinical data on the sequentialuse of aromatase inhibitors (AI). This paper focuses on therelevance of clinical benefit CB (CR + PR + SD 6 months) inpostmenopausal metastatic breast cancer (MBC) patients treated with thesteroidal aromatase inhibitor (SAI) formestane (FOR), who had alreadyreceived non-steroidal aromatase inhibitor (nSAI): letrozole (LTZ) oranastrozole (ANZ). Patients and methods:Twentypostmenopausal women with MBC were analysed in this retrospectivetwo-centre study with the sequence nSAI-FOR. When receiving ANZ, 1 of 11achieved a complete response and 9 of 11 a stable disease 6 months,and receiving LTZ 1 of 9 achieved a partial response and 4 of 9 astable disease 6 months. The analysis of the entire populationtreated with FOR showed an overall CB of 55% (11 of 20) with amedian duration of 15 months and median time to progression (TTP) of 6months. Conclusions:Formestane 250 mg once bi-weeklyseems to be an attractive alternative third-line hormonal therapy forthe treatment of patients with MBC, previously treated with nSAI.     

Are medical oncologists biased in their treatment of the large woman with breast cancer?

Purpose. Obesity and breast cancer are common conditions that often coexist. Concerns of relative overdosing of chemotherapy in the large cancer patient have led clinicians to apply empiric dose reductions, cap the body surface area (BSA) at 2m², or use ideal rather than actual body weight to calculate BSA. There are no data supporting or refuting these practices and their prevalence is unknown. We sought to determine the distribution of body size and prevalence of obesity in the breast cancer population of our cancer centre, and to determine clinician chemotherapy dosing practices in the era of modern adjuvant chemotherapy. Patients and methods. Women with invasive breast cancer receiving systemic therapy at our institution between 1980 and 1998 were identified and their recorded height and weight were used to calculate BSA and body mass index (BMI). We reviewed the first cycle adjuvant chemotherapy dosing practices from 1990–1998. The ideal dose of chemotherapy was calculated based on calculated BSA, and then contrasted with the actual dose received at cycle one. Discrepancies were recorded and categorized, using the largest single drug reduction if more than one drug was reduced. Results. Mean BMI in the systemic therapy population was 26.4±5.3kg/m², 54% were overweight, 2% severely obese and 18% moderately so. Their mean BSA was 1.7±0.2m² and only 5% had a BSA2m². In the adjuvant chemotherapy subgroup, most patients received >85% of their ideal dose. The mean dose reduction was 5.3±11.3% versus 9.9±11.3% in the BSA <2 and >2m² groups, respectively (p=0.02), and 4.3±8.2% versus 6.7±13.1% in the BMI <25 and 25kg/m² groups, respectively (p=0.008). While only 24% of chemotherapy dose reductions of 15% were in the BSA 2m² group, 76% were in the BMI 25kg/m² group. Conclusions. Obesity is prevalent in this breast cancer population. BSA is not a sensitive index of large body size. We consistently detected more frequent empiric dose reductions at cycle one of adjuvant chemotherapy, with reductions of greater magnitude in the largest women (BSA 2m²) and those who were overweight (BMI 25kg/m²).     

Survival of women after breast conserving surgery for early stage breast cancer

Background. Increasing numbers of older women with breast cancer are receiving breast-conserving surgery (BCS). However, substantial numbers of them are not receiving either axillary dissection or adjuvant irradiation. Objective. To determine whether failure to perform axillary dissection or irradiation is associated with decreased survival in women with early-stage breast cancer. Method. We studied 26,290 women aged 25 in 1988-1993 from the surveillance, epidemiology, and end results (SEER) data and 5,328 women aged 65 in 1991-1993 from SEER-Medicare linked data, who had early-stage breast cancer and received BCS. Results. Twenty seven percent of women aged 25 receiving BCS did not receive axillary dissection, most of whom (74%) were age 65. Women receiving BCS with axillary dissection had lower 7-year breast cancer-specific mortality than did those without dissection (hazard ratio=0.53, 95% confidence interval: 0.44–0.63). We found an interaction between receipt of axillary dissection and radiotherapy on survival of older women after BCS. Women who received either axillary dissection or radiotherapy experienced similar survivals to those who received both axillary dissection and radiation, while women who received neither treatment experienced poorer survival (hazard ratio=1.76, 1.23–2.52), after controlling for demographics, tumor size and comorbidity. Conclusions. Women who receive neither axillary dissection nor radiation therapy after BCS experience an increased risk of death from breast cancer. The lack of improvement in the past two decades in survival of older women with breast cancer may be explained in part by the increasing use of treatments that do not address potential tumor in axillary nodes.     

Hormone receptors and obesity in Japanese women with breast cancer

Summary An association between hormone receptors in primary breast cancer and obesity determined prior to mastectomy was investigated in 128 Japanese women. The following criteria for obesity were used: (1) weight 60 kg (132 lbs), (2) weight kg/height cm–105 1.3, (3) weight lbs/height in 2.30, (4) body surface area 1.56 m². In view of the 4 criteria, tumor estrogen receptor (ER) values 4 fmol/mg were observed in obese patients more often than in nonobese patients, though the difference was not statistically significant. The same tendency was observed in the postmenopausal subgroup, 62 patients, especially in the 36 patients more than 5 years beyond menopause. However, there was still no statistical difference between obese and nonobese patients because the number of subjects was small. The same tendency was observed in the case of progesterone receptor (PgR) (6 fmol/mg) as observed in the case of ER. Address for reprints: Dr. Keijiro Kuno, Department of Surgery, Cancer Institute Hospital, 1-37-1 Kami-Ikebukuro, Toshima-ku, Tokyo, Japan 170     

Effects of mammographic density and benign breast disease on breast cancer risk (United States)

Background: Having either a history of benign breast disease, particularly atypical hyperplasia or extensive mammographic breast density, is associated with increased breast cancer risk. Previous studies have described an association between benign breast disease histology and breast density. However, whether these features measure the same risk, or are independent risk factors, has not been addressed. Methods: This case–control study, nested within the prospective follow-up of the Breast Cancer Detection Demonstration Project, evaluated both benign histologic and mammographic density information from 347 women who later developed breast cancer and 410 age- and race-matched controls without breast cancer. Multivariate logistic regression analyses provided maximum-likelihood estimates of the odds ratios (OR) and 95% confidence intervals (CI) to evaluate the relative risk of breast cancer associated with each exposure. Results: Adjusting for mammographic density, the OR for atypical hyperplasia was 2.1 (95% CI: 1.3–3.6), and adjusting for benign breast histology, the OR for 75% density was 3.8 (95% CI: 2.0–7.2). Women with nonproliferative benign breast disease and 75% density had an OR of 5.8 (95% CI: 1.8–18.6), and women with <50% density and atypical hyperplasia had an OR of 4.1 (95% CI: 2.1–8.0). Conclusions: In this study, both benign breast disease histology and the percentage of the breast area with mammographic density were associated with breast cancer risk. However, women with both proliferative benign breast disease and 75% density were not at as high a risk of breast cancer due to the combination of effects (p = 0.002) as women with only one of these factors.     

Modulating effect of lonidamine on response to doxorubicin in metastatic breast cancer patients: Results from a multicenter prospective randomized trial

Previous results from our preclinical studies have shown that lonidamine (LND) can positively modulate the antiproliferative activity of doxorubicin (DOX) on breast cancer cell lines. To evaluate the effect of LND in a clinical setting, a multicenter randomized trial was carried out on patients with advanced breast cancer. From September 1991 to July 1993, 181 patients were enrolled in the trial and received an initial treatment of DOX at 75 mg/m² for 3 cycles. The 137 patients who reached complete remission, partial remission, or stable disease were randomized to receive either DOX alone (75 mg/m² day 1) (arm A) or DOX plus LND (600 mg orally/day) (arm B).The patients enrolled in the two arms were fairly homogeneous in terms of major clinical characteristics. Toxicity was similar in both arms except for myalgia: WHO grade 2 was observed in 57% of arm B patients. Overall response rate to DOX + LND was 50% and to DOX alone 38% in evaluable patients, and 48% vs 37% in all registered patients, as determined by an intention-to-treat analysis. The differences did not reach statistical significance. Conversely, in agreement with previous findings, we observed a significant difference in response rate in the subgroup of patients with liver metastases, regardless of the extent of hepatic involvement (DOX + LND 68% vs DOX 33%, p=0.03). This observation makes LND an important tool in association with anthracyclines in the treatment of this subgroup of patients.     

Combined effect of tobacco and alcohol on laryngeal cancer risk: a case-control study

Objective: To provide information on the effects of alcohol and tobacco on laryngeal cancer and its subsites. Methods: This was a case–control study conducted between 1992 and 2000 in northern Italy and Switzerland. A total of 527 cases of incident squamous-cell carcinoma of the larynx and 1297 hospital controls frequency-matched with cases on age, sex, and area of residence were included. Odds ratios (ORs) and corresponding 95% confidence intervals (CIs) were estimated using multiple logistic regression. Results: In comparison with never smokers, ORs were 19.8 for current smokers and 7.0 for ex-smokers. The risk increased in relation to the number of cigarettes (OR = 42.9 for 25 cigarettes/day) and for duration of smoking (OR = 37.2 for 40 years). For alcohol, the risk increased in relation to number of drinks (OR = 5.9 for 56 drinks per week). Combined alcohol and tobacco consumption showed a multiplicative (OR = 177) rather than an additive risk. For current smokers and current drinkers the risk was higher for supraglottis (ORs 54.9 and 2.6, respectively) than for glottis (ORs 7.4 and 1.8) and others subsites (ORs 10.9 and 1.9). Conclusions: Our study shows that both cigarette smoking and alcohol drinking are independent risk factors for laryngeal cancer. Heavy consumption of alcohol and cigarettes determined a multiplicative risk increase, possibly suggesting biological synergy.     

Prognostic Significance of Tumor Cell Proliferation Analyzed in Fine Needle Aspirates from Primary Breast Cancer

The objective of this study was to analyze the role of proliferating fraction (PF) measured with Ki-67/MIB-1 antibody in a large series of preoperative fine-needle aspirate (FNA) biopsies as a prognosticator of disease recurrence. The study comprised 732 patients who all had a conclusive cytological diagnosis of breast cancer. The follow-up time ranged from 1.2 to 10.2 years with a median of 5.7 years. In multivariate analysis Ki-67/MIB-1 value was a strong (p<0.001) significant, prognosticator of disease recurrence free interval (DRFI) independent of lymph node status, progesterone receptor content, and tumor size. In the subgroup analysis of 430 node-negative patients the distant recurrence-free rate after 5 years was 94.4% in patients with Ki-67/MIB-1 value<15% compared to 88.7% in patients with Ki-67/MIB-1 value 15% (p=0.03). Test of the interaction between tumor size and the value of PF revealed a p-value of 0.06. If the patients, in addition, had a tumor size 20mm the distant recurrence-free rate after 5 years was 93.2% if Ki-67/MIB-1<15% compared to 80.7% in patients with Ki-67/MIB-1 value 15%. This difference was statistically significant (p<0.01). For patients with tumors <20mm Ki-67/MIB-1 value did not add any prognostic information. In the subgroup of 302 node-positive patients the distant recurrence-free rate after 5years was 86.0% in patients with Ki-67/MIB-1 value<15% compared to 70.6% in patients with Ki-67/MIB-1 value 15% (p<0.01). We conclude that PF assessed by Ki-67/MIB-1 antibodies in preoperative FNA biopsies has a significant prognostic value independent of lymph node status, PgR status and tumor size. To our knowledge, this is the first study demonstrating PF, which can contribute prognostic information when analyzed in preoperative smears.     

The polymorphic CAG repeat of the androgen receptor gene: a potential role in breast cancer in women over 40

Previous investigations into the relationship of CAG-repeat lengths in the androgen receptor (AR) gene to female breast cancer (BC) have yielded somewhat confusing results. Decreased AR transactivational activity lowers androgen:estrogen balance, and may thereby effect functional hyperestrogenicity. This may promote the pathogenesis of BC. To elucidate whether longer CAG repeats of the AR gene (AR), which correlate with lower transactivational activity of the AR, are associated with BC in women over 40, we examined the distribution of CAG-repeat lengths in BC tissue from this population. The BC tissue was histologically graded as: Grade 1, well differentiated (WD); Grade 2, moderately differentiated (MD); and Grade 3, poorly-differentiated (PD). Analysis showed significant differences as compared to controls when CAG lengths greater than 21 were examined, and that alleles with 26 repeats were 2.4-fold more frequent in BC samples than in constitutional samples from a normal population. A significant shift to greater CAG-repeat lengths, appeared in WD and MD tumors only. Our results give some indication as to the progression of BC by suggesting that hypotransactive ARs with long polyglutamine (polyGln) tracts may have a role in the initiation and/or progression of BC. PD tumors tended to have shorter than normal CAG-repeat lengths. In this case it is hypothesized that the ARs have now become hypertransactive, possibly coinciding with the estrogen resistance that is associated with PD tumors. Whether this shift is of germline or somatic origin was not clear, though the appearance in 14% of the BC samples of a third CAG-repeat length indicates that it may be somatic.     

Increasing body mass index in Japanese patients with gastric cancer

We studied the body mass index (BMI) of 986 patients who underwent potentially curative gastrectomy for gastric cancer at the National Cancer Center Hospital, Tokyo, in 1971, 1981, 1991, and 2001. The median BMI increased from 20.8kg/m² in 1971 to 22.6kg/m² in 2001 (P, 0.01). The increase was significant in both early and advanced gastric cancers, and in males, but not in females. The proportion of overweight patients (BMI 25.0kg/m²) increased from 9.2% in 1971 to 24.0% in 2001. Obese patients (BMI 30.0kg/m²) were rare. In conclusion, surgeons at the National Cancer Center Hospital, Tokyo, are increasingly having to operate on fat patients, but obese patients are still uncommon compared to the West.     

Intrathecal Chemotherapy with MX2 for Treating Glioma Dissemination in vivo

We examined whether the intrathecal MX2 chemotherapy for treating dissemination of malignant glioma would be a feasible therapy. In the toxicity study, physiological and histological neurotoxicity was not observed in the rats treated with less than 100g/kg of MX2 administered intracisternally. But physiological side effects were observed in the treatment group of more than 200g/kg and histological brain toxicity was in the treatment group of more than 1000g/kg. Dissemination models were induced in rats by intracisternal inoculation of C6 glioma cells. The median survival times of the rats treated with 100g/kg of intrathecal MX2 on day 1, 3, or 7 after tumor inoculation were prolonged by 52.4% (p=0.0006), 31.5% (p=0.0007), and 7.1% (p=0.0180), respectively, compared to that of untreated control animals. Intrathecal MX2 treatment also cured 33.6% of rats in the treatment group. These findings suggested that there was a possibility that intrathecal MX2 would be a safe and effective method for treating dissemination of malignant glioma.     

Concurrent Accelerated Hyperfractionated Radiation Therapy and Carboplatin/etoposide in Patients With Malignant Glioma: Long-term break Results of A Phase II Study

Purpose: Feasibility, antitumor activity and toxicity of accelerated hyperfractionated radiation therapy (Acc Hfx RT) and concurrent carboplatin/etoposide (CBDCA/VP 16) chemotherapy were investigated in patients with malignant glioma. Material and methods: Seventy-nine patients with either glioblastoma multiforme (GBM) (n = 61) or anaplastic astrocytome (AA) (n = 18) entered into a phase II study on the use of Acc Hfx RT with 60Gy in 40 fractions in 20 treatment days over 4 weeks and concurrent CBDCA, 200mg/m², and VP 16, 200mg/m², both given once weekly during the RT course. Results: The median survival time for all 79 patients was 14 months (11 and 44 months for GBM and AA patients, respectively), while the 2- and 4-year survival was respectively 33% and 11% for all patients, 13% and 1.6% for GBM patients, and 100% and 44% for AA patients (p < 0.0001). The median time to progression for all patients was 12 months (9 and 40 months for GBM and AA, respectively), while the 2- and 4-year progression-free survival (PFS) was respectively 28% and 10% (all patients), 10% and 1.7% (GBM) and 89% and 39% (AA) (p < 0.0001). Multivariate analysis showed that age, performance status, and preoperative size of tumor influenced survival in GBM. Only 5 (6%) patients experienced grade 3 leukopenia and 6 (8%) patients experienced grade 3 thrombocytopenia. No late RT-induced toxicity was observed to date. Conclusions: Although Acc Hfx RT/CBDCA + VP 16 was feasible and little toxic, it failed to improve survival/progression-free survival over that obtained with other currently used regimens. These results do not justify the investigation of this regimen in a phase III trial.     

Effect of timing of initiation of adjuvant chemotherapy on disease-free survival in breast cancer

Summary Four hundred and sixty patients with stage II or III breast cancer following regional therapy were treated with an adjuvant combination chemotherapy consisting of fluorouracil, doxorubicin, and cyclophosphamide (FAC). The relationship between the length of disease-free survival and length of delays in initiation of chemotherapy after surgery was evaluated. Patients were divided into four subgroups according to the length of delay in initiation of chemotherapy (< 10 weeks, 10–13, 14–17, and 18 weeks). Overall four year diseasefree survival was 64%, 68%, 60%, and 63% for patient groups with delays of < 10 weeks, 10–13, 14–17, or 18 weeks respectively (p = 0.39). There was no trend for longer delay in treatment to be associated with shorter disease-free survival, except in poor prognosis patients.     

Prognostic significance of thymidylate synthase in patients with metastatic colorectal cancer who receive protracted venous infusions of 5-fluorouracil

Background This study was conducted to evaluate the prognostic significance of thymidylate synthase (TS) expression in the tumor tissue of patients with metastatic colorectal cancer (CRC) who received protracted venous infusions of 5-fluorouracil (5-FU).Methods We retrospectively analyzed the prognostic value of TS expression as compared with other clinical prognostic factors in 57 patients with metastatic CRC.Results On univariate analysis, survival was significantly related to TS expression (low vs high; P = 0.0015), alkaline phosphatase (ALP) level (<300 vs 300IU/l; P = 0.0037), performance status (0 or 1 vs 2 or 3; P = 0.0073), and white blood cell count (<10000/mm³ vs 10000/mm³; P = 0.0001), with number of metastatic sites (1 vs 2; P = 0.06) approaching significance. On multivariate analysis, survival was significantly related to TS expression (hazard ratio [HR], 2.97) and ALP level (HR, 2.26).Conclusion In patients with metastatic CRC who received protracted venous infusions of 5-FU, TS expression was related to survival independently of other established clinical prognostic factors.     

Postoperative Radiation Therapy for Medulloblastoma – High Recurrence Rate in the Subfrontal Region

Purpose: To investigate the treatment results and analyze the prognostic factors for patients with medulloblastoma (MB) treated by surgery and postoperative radiation therapy (RT). Methods and Materials: Thirty-five patients of MB receiving surgery followed by RT from February 1986 to September 1999 were reviewed. Their median age was 12 years with a slight male predominance. Twenty-four (69%) patients had total resection of tumor. Most (86%) cases received craniospinal irradiation (CSI). Adequate dose (craniospinal dose 30Gy and posterior fossa dose 50Gy) was given in 26 (74%) patients. Results: The median survival duration was 48 months. The 5-year and 10-year overall survival rates were 63% and 40%, respectively. Univariate analysis revealed that stage, shunt surgery, RT dose, and protracted RT course were significant factors in predicting overall survival (OS), disease-free survival (DFS), and/or posterior fossa control (PFC). Multivariate analysis showed that RT dose affected OS and PFC independently, stage influenced OS and DFS, while protracted RT course impacted DFS. A total of 20 cases developed disease relapse. The median time to relapse was 18 months. The posterior fossa (10 cases) was the most common site of first failure, followed by the subfrontal lobe (7 cases), spine (6 cases), and other areas (4 cases). Conclusion: Our results were compatible with others, except that more subfrontal relapses were found. Surgical resection followed by standard dose and adequate margin of CSI are recommended as the mainstays of treatment.     

Association of folate and alcohol with risk of ovarian cancer in a prospective study of postmenopausal women

Studies evaluating the association of ovarian cancer with alcohol intake are inconsistent, and few have evaluated this association in the context of folate consumption. Dietary folate and alcohol intakes and lifestyle and medical information were collected with self-administered questionnaires in 1986 from postmenopausal women aged 55–69 followed prospectively for 15 years for risk of epithelial ovarian cancer in the Iowa Women's Health Study. Among 27,205 eligible women free of baseline cancer, 147 incident epithelial ovarian cancer cases were identified by linkage to a cancer registry. Compared to the lowest quartile of total folate (food plus supplement) intake, the multivariable risk ratios (RR) for increasing quartiles were 1.0 (referent), 1.59, 1.24, 1.73 (95% confidence interval [CI], 0.90–3.33; p for trend, 0.20). Compared to non-drinkers, the RRs for increasing alcohol intake were 1.0 (referent), 0.78 for 0.01–3.9 g/d, 0.75 for 4.0–9.9 g/d and 0.58 for 10 g/d (95% CI, 0.30–1.11; p for trend, 0.08). Among women with alcohol intake 4 g/d compared to <4 g/d, the apparent risk reduction was limited to those with total folate intake 331 g/d (RR, 0.52; 95% CI, 0.22–1.19; p for interaction, 0.04) although this estimate was based on only seven cases. The association did not change appreciably when we excluded tumors of mucinous histology. These findings suggest that alcohol consumption is inversely related to postmenopausal ovarian cancer, and that the association of folate with ovarian cancer may vary by the amount of alcohol consumed.     

Capecitabine and oxaliplatin in advanced colorectal cancer:A?dose-finding?study

Purpose:Capecitabine and oxaliplatin are both activeanticancer agents in the treatment of patients with advanced colorectalcancer (ACRC). The aim of this dose-finding trial was to determinethe maximum-tolerated dose (MTD), the dose-limiting toxicities (DLTs)and the activity of the combination in patients with advanced colorectalcancer. Patients and methods:Twenty-fivechemotherapy-pretreated patients received the combination ofcapecitabine and oxaliplatin. Capecitabine was administered orally twicea day continuously for 14 days in doses ranging from 1650 to 2500mg/m²/d, and oxaliplatin was administered as a two-hourinfusion on day 1 using dose, ranges from 100 to 130 mg/m²repeated every three weeks. Results:Twenty-fivepatients were assessable for toxicity, and DLTs were diarrhea (grade3: 27%) and stomatitis (grade 3: 9%) at dose levelVI. Dose level V (capecitabine 2500 mg/m² and oxaliplatin 120mg/m²) was found to be the MTD. Hematological toxicitywas minimal, overall neurotoxicity (grade 1–4) was 27% with1% grade 3–4. A global response rate was 17%(95% confidence interval (95% CI):2%–32%) and the median overall survival was 12months. Conclusion:The recommended dose for furtherphase II studies is capecitabine 2500 mg/m²/d withintermittent schedule and oxaliplatin 120 mg/m² every threeweeks. The toxicities were mainly gastrointestinal: diarrhea, stomatitisand vomiting. This combination should be studied in phase II trials inadvanced colorectal.     

CEA and CA?19-9 measurement as a monitoring parameter in metastatic colorectal cancer (CRC) under palliative first-line chemotherapy with weekly 24-hour infusion of high-dose 5-fluorouracil (5-FU) and folinic acid (FA)

Background:There have been contradictory reports on the benefitof CEA and CA 19-9 measurements in patients with metastatic colorectalcancer using palliative chemotherapy. The object of this study was to examinethe diagnostic accuracy of monitoring of palliative chemotherapy by means ofCEA and CA 19-9. Patients and methods:The tumour markers CEA and CA 19-9 weresubjected to serial measurement in patients with metastatic colorectal cancer(n = 90) using palliative first-line chemotherapy with weekly 24-hourinfusion of high-dose 5-FU with FA and were compared with objective responseaccording to WHO criteria. 85 patients could be evaluated. 43 patients(51%) initially had elevated CEA (10 ng/ml) and 33 patients(39%) elevated CA 19-9 (50 IE/ml). In 24 patients(28%), both markers were initially increased. With CEA positivepatients, 143 cycles of chemotherapy were carried out, which showed thefollowing response in the various cycles: 21 episodes with progressions (ePD),69 episodes with no change (eNC), 53 episodes with partial/complete remission(ePR/eCR). With CA 19-9 positive patients, 100 cycles of chemotherapywere carried out with the following results: 21 episodes with progressions(ePD), 48 episodes with eNC, and 31 episodes with ePR/eCR. Results:A CEA rise by at least 50% differentiated betweenePD versuseNC/ePR/eCR with a sensitivity of 76% andspecificity of 90%. With CEA decreases of at least 30% in99% of these patient episodes (78 of 79), a tumour progression couldbe excluded. Patients with an initial drop in CEA after the first cycle ofchemotherapy of at least 50% of the initial level had a significantlyhigher probability of achieving an ePR/eCR in further therapy (relative risk2.9; P = 0.002). With an CA 19-9 increase of at least30%, a sensitivity progression of 62% and a specifity of90% could be calculated. A CA 19-9 decrease of at least 60%excludes a progression in 95% of the patient episodes. Conclusions:A CEA or CA 19-9 rise is only conditionallyappropriate for recording progressions. A progression however, can be excludedwith falling levels with high diagnostic accuracy, in which CEA offers agreater degree of certainty than CA 19-9. With a drop in CEA 79 of 143(= 55%) of the CT scans could be saved, in which case 78 of 79 patientepisodes (99%) were correctly assessed as 'no progression'.In patients with an increased CEA and CA 19-9 the CEA determination issufficient for the further monitoring. A confirmation of these results bymulticenter trials can result in a considerable decrease of monitoring costsfor palliative treatment.